Ion-ARPA request for proposals
Strategies for Increasing ASO On-Rate In Vivo

The therapeutic performance of antisense oligonucleotides (ASOs) in vivo is potentially limited not by equilibrium binding affinity, but by the kinetics of productive target engagement (on rate). Within cells, ASOs encounter a highly crowded and heterogeneous environment characterized by low effective target concentrations, extensive RNA secondary and tertiary structure, competition from abundant non-target RNAs, and restricted temporal access to relevant subcellular compartments. Despite its importance, ASO on-rate optimization remains underexplored relative to affinity and stability engineering, representing a potentially significant opportunity for innovation in antisense therapeutics. This request for proposals seeks novel ideas to increase the on-rate of ASOs.

Funding and Project Period Award Size: Up to $500,000 total direct and indirect costs per year for up to 2 years, renewable with successful progress.


Funding Structure: Awards are structured with defined milestones and continuation criteria. Second year funding may be contingent on satisfactory progress toward performance objectives.

Key Dates: 

  • Program announcement: April 1, 2026
  • White papers due: July 1, 2026
  • Full proposals due: September 1, 2026
  • Award announcements: November 15, 2026
  • Funding start: Immediately following award announcement and finalizing contract
     

Submissions

To minimize the burden of grant preparation, our review process emphasizes the strength and originality of the proposed approach rather than exhaustive proposal documentation. Investigators interested in funding are invited to submit a concise white paper (maximum 5 pages) describing the core idea and its scientific rationale. In many cases, funding decisions will be made primarily on the basis of the white paper, with more detailed materials such as a full statement of work, milestone plans, and detailed budgets requested only after an intention to proceed has been made.

Teaming is encouraged but not required. Responsive solutions often require integration of expertise from diverse disciplines. Investigators from different institutions will each be funded directly from Ionis but will be reviewed as a team. During the course of the programs, we find that Ionis scientists often collaborate with our partners by providing scientific input, specialized materials, or conducting testing of partners' compounds in our disease models.

Use the standard white paper template and submit to [email protected]. If you would like to discuss your concept in advance of submitting a white paper, please reach out to us for a pre-white paper discussion at the same address.

Intellectual Property

The awardees will retain ownership of intellectual property created during performance of the program. In exchange for its funding, Ionis will receive a paid-up, non-exclusive license (with sublicensing rights to affiliates only) and first option to negotiate for an exclusive license.

Scope Clarification: What This RFP Is Not Seeking

To focus proposals on the intended kinetic objective, the following areas are out of scope unless explicitly tied to demonstrable increases in on-rate:

  • Approaches that primarily increase equilibrium binding affinity (Kd) without addressing binding kinetics
  • Strategies focused solely on slowing dissociation (off-rate) once duplex formation has occurred
  • Improvements limited to chemical stability, nuclease resistance, or plasma half-life without effects on target engagement kinetics
  • Delivery strategies that increase total cellular ASO uptake but do not alter the probability or speed of productive target binding
  • In vitro affinity improvements that do not translate to measurable kinetic gains in cellular or in vivo contexts
     

Proposals should clearly articulate how the proposed approach increases the frequency or speed of productive ASO–target encounters, rather than merely stabilizing the bound state.

Illustrative Areas of Interest (Non-Prescriptive)


Applicants are encouraged to propose innovative and unconventional approaches. Relevant, but not limiting, areas of interest include:
 

  • Chemical or structural pre-organization of ASOs to produce seed regions in a "hybridization-ready" state (as in Ago2) to reduce activation barriers for target binding, such as designing a mini-Ago-like conjugate that presents the oligo in that form.
  • Protection mechanisms to prevent ASO nucleotides from unproductive interactions with non-target RNA and non-nucleic acid cellular components.
  • Kinetic gating or proofreading mechanisms that bias ASOs toward correct targets by suppressing nonproductive encounters with non-target RNAs.
  • Transient target remodeling strategies that increase accessibility or reduce structural barriers at the moment of binding.
  • Biophysical modulation of local search processes, including effects on diffusion, confinement, or subcellular localization that directly enhance encounter rates. Chemical excipients are not considered a suitable approach.
  • Coupling of reagents that enable one-dimensional searches along mRNAs (in a fashion similar to how restriction enzymes find their targets)

Identifying concepts from nature and adapting them into engineered ASO design may be a productive route. For example, restriction enzymes accelerate target recognition by coupling weak nonspecific binding to one-dimensional search along nucleic acid polymers, suggesting that analogous dimensionality-reduction strategies could substantially increase ASO on-rates in vivo without increasing affinity or reducing off-rates.


Proposals may draw from chemistry, structural biology, biophysics, cell biology, or computational modeling, but should include a clear hypothesis linking the approach to increased ASO on-rate in vivo.

Evaluation Criteria

Proposals will be evaluated on novelty, mechanistic rigor, and the plausibility of achieving meaningful increases in ASO on-rate under physiologically relevant cellular or in vivo conditions, with emphasis on mechanistic clarity and translational relevance rather than incremental optimization:

  1. Relevance to On-Rate Enhancement (Primary Criterion)
    • Clear and compelling rationale for how the proposed approach increases the on-rate of productive ASO–target binding in vivo
    • Explicit distinction between effects on on-rate versus equilibrium affinity, off-rate, or delivery alone
    • Appropriateness of experimental systems used to assess on-rate under physiologically relevant conditions
       
  2. Mechanistic Insight and Scientific Rigor
    • Strength of the underlying hypothesis and supporting evidence
    • Use of quantitative or kinetic frameworks to interpret results
    • Ability to distinguish productive binding events from nonproductive or transient interactions
       
  3. Innovation and Originality
    • Novelty of the conceptual approach, methodology, or design paradigm
    • Willingness to challenge prevailing assumptions in antisense design
    • Potential to open new directions beyond established ASO optimization strategies
       
  4. Translational Plausibility
    • Likelihood that the proposed strategy could be implemented in therapeutically relevant ASO chemistries and formats
    • Consideration of scalability, manufacturability, and compatibility with existing antisense platforms
    • Evidence that observed effects are not restricted to narrowly defined in vitro systems
       
  5. Experimental Feasibility and Milestones
    • Appropriateness of the proposed timeline and milestones for a two-year project
    • Clear go/no-go decision points and success criteria
    • Alignment between requested budget and proposed scope of work
       
  6. Team Expertise and Environment
    • Demonstrated expertise in relevant disciplines (e.g., oligonucleotide chemistry, biophysics, RNA biology, quantitative kinetics, or cellular pharmacology)
    • Adequacy of institutional resources to execute the proposed research
    • Evidence of interdisciplinary integration where appropriate